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Posted: July 7, 2006

Targeting the threat of thrombosis at the molecular level

(Nanowerk News) New research at The University of Nottingham in the UK could help to prevent the harmful blood clots associated with heart disease and stroke.

Scientists have gained new insights into the coagulation of blood, in a study which could pave the way for new treatments aimed at preventing thrombosis — clots in the blood that obstruct the flow of blood through the circulatory system.

The UK has one of the highest rates of death from heart disease in the world: one British adult dies from the disease every three minutes, and stroke is the country's third biggest killer, claiming 70,000 lives each year.

These conditions arise from defects in the process of blood coagulation in the heart or brain. The plasma protein Factor XI (FXI) is a key culprit in this process — it can trigger the development of harmful blood clots, known as thrombi.

Now, for the first time, in a study funded by the British Heart Foundation, University of Nottingham scientists have revealed the molecular structure of FXI. The discovery of its structure marks a major step forward on the way to new drugs and treatments to tackle thrombosis.

FXI is unique among coagulation factors since it consists of two identical subunits that are joined together in a structure termed a dimer. Researchers knew that the FXI dimer circulates in an inactive form and must bind to certain other cells to become active. But the significance of its unique molecular characteristics had baffled scientists for decades.

A team led by Dr Jonas Emsley at The University of Nottingham Centre for Biomolecular Sciences, in collaboration with Professor Peter Walsh from Temple University in Philadelphia, USA, has made a breakthrough by determining the molecular structure of FXI.

They have discovered that the molecule has an unusual "cup and saucer" shape with the apple domains associating to form a ring-like architecture (the saucer), that cradles the active part of the molecule (the cup), termed the protease domain. Observations of the structure imply that the FXI molecule behaves like a 'nano-machine', and on exposure to injury the apple domain ring (or saucer) undergoes major spring-like changes, when the molecule is activated by platelets in the blood.

Dr Jonas Emsley, Associate Professor and Reader in Crystallography at The University of Nottingham, said: “FXI is of great therapeutic interest in the drive to discover novel anticoagulant therapies.

“What is exciting about targeting proteins like FXI is that studies in mice, in which the related gene is 'switched off', show that the absence of FXI leads to otherwise healthy animals which do not form harmful thrombi.

“This strongly implies that anti-coagulant properties of drugs targeted at FXI to prevent or treat thrombosis — ie. heart attacks, strokes or pulmonary emboli — would not necessarily have the side effects, such as bleeding, associated with current treatments such as heparin or oral anticoagulants. Current treatments target multiple coagulation proteins which have a more central role in healthy blood clotting and hence are more prone to side effects.

“However, one obvious question arising from the studies in mice is that FXI cannot simply be functioning to cause disease — it must also have a beneficial effect to health. It seems likely that FXI only swings into action when a person suffers a major injury or trauma, and where there is a requirement for large quantities of blood clotting.”

The new study is published in the journal Nature Structural and Molecular Biology and was funded by the British Heart Foundation from the National Institutes of Health in the U.S.

Dr Emsley added that although the FXI structure represents a big step forward in understanding this important protein, it will require many more years of hard work to design and synthesise inhibitors that dock into the structure and can be translated into successful clinical drugs.